2007 Nature Publishing Group

The classical Greek term pharmakon

indicates that a substance can be a remedy
as well as a poison, and in many traditional
societies cannabis was considered to have
both of these properties. However, as the
twentieth century progressed, cannabis
gradually lost its status as a useful remedy,
and fewer and fewer people regarded it as
harmful. Indeed, by the 1990s, the prevail-
ing medical wisdom held that smoking
cannabis did not cause long-term harm to
health
1
. Recreational use became normal-
ized to the extent that use of cannabis was
seen, like that of alcohol, nicotine and
caffeine, as a culturally acceptable lifestyle
choice [MFLNF}.
Recently, however, cannabis has re-
emerged as both a potential medicine and a
potentially harmful drug. On the one hand,
cannabis-based drugs have been shown to
be of value to people with chronic pain, and
to control spasticity in patients with multiple
sclerosis
2
. On the other hand, a number of
reports have claimed that heavy use of can-
nabis increases the risk of psychotic illnesses,
such as schizophrenia. If the latter is true
for even a small minority of cannabis users,
this would be of considerable public health
importance, because cannabis is the worlds
third most-popular recreational drug [FC !},
after alcohol and tobacco.
In this Perspective, we briefly outline
recent research into the endocannabinoid
system
38
and discuss how exogenous can-
nabinoids might disrupt interneuronal
signalling and information processing in
the brain. We then consider the evidence as
to whether cannabis can induce acute and
chronic psychosis, whether it is addictive
and whether its use leads on to the use of
hard drugs, such as heroin and cocaine.
Finally, we discuss how different societies are
attempting to deal with cannabis use.
The endocannabinoid system
The major psychoactive ingredient of can-
nabis is
9
-tetrahydrocannabinol (THC),
the structure of which was elucidated by
Raphael Mechoulam and colleagues in
the 1960s
9
. THC elicits its psychological
effects by stimulation of the cannabinoid 1
(CB1) receptor
10
, which was identified in
1988 [RFF !!} and cloned in 1990 [RFF !2}.
The CB1 receptor is the most common
G-protein-coupled receptor in the brain
7
.
Its expression is particularly high in the
hippocampus, the cerebellum, the basal
ganglia and the neocortex, consistent with
the major psychological and motor effects
of THC administration
1316
. Expression of
CB1 in peripheral nerve fibres, the dorsal
root ganglion, the spinal dorsal horn and
the peri-aquaductal grey probably accounts
for the analgesic properties of THC
1719
. A
second cannabinoid receptor, CB2 [RFF 20},
which was once believed to be restricted
to immune cells, is also expressed in CNS
neurons, although at lower levels than CB1
receptors
2123
.
The discovery of these receptors
prompted a search for their endogenous ago-
nists. The first of these endocannabinoids to
be discovered, arachidonoylethanolamide,
was termed anandamide, from the Sanskrit
word ananda, signifying bliss
24
. A second
endocannabinoid, 2-arachidonoylglycerol,
was discovered in 1995 [RFFS 25,26}, and
others soon followed. Unlike conventional
neurotransmitters, endocannabinoids are
not stored in vesicles, but are synthesized on
demand from membrane phospholipids
6
.
Endocannabinoids act as retrograde
signals at CNS synapses
8,27
[FC 2a}. They
are synthesized in dendrites but act
presynaptically to inhibit the release of
fast-acting amino-acid neurotransmitters.
Ultrastructural analyses have located key
enzymes for endocannabinoid synthesis
at dendritic spines, and have detected CB1
receptors on the terminals of neighbouring
GABA (-aminobutyric acid)-releasing and
glutamatergic neurons
15,28,29
. In the neocor-
tex, the striatum and the hippocampus, CB1-
receptor expression is considerably higher
on GABA-releasing than on glutamatergic
terminals
15,16,30,31
. The reason for this, and
whether this pattern is seen throughout the
CNS, remains unknown. However, this fact
might explain the bidirectional effects of
THC, and also why, for example, THC can
be either pro- or anti-convulsant, depending
on the dose
32,33
.
Endocannabinoids are synthesized by
principal output neurons, such as Purkinje
cells in the cerebellum, pyramidal neurons
in the hippocampus and the cortex, medium
spiny neurons in the striatum, and dopamin-
ergic neurons in the midbrain
34
. It seems
that these neurons regulate their excitatory
and inhibitory inputs by releasing endocan-
nabinoids. In this way, endocannabinoids
add another layer of modulation of plasticity
at glutamate synapses to that which is pro-
vided by conventional transmitters, such as
dopamine and serotonin
35
.
SCI ENCE AND SOCI ETY
Cannabis, the mind and society:
the hash realities
Robin M. Murray, Paul D. Morrison, Ccile Henquet and Marta Di Forti
Abstract | Cannabis has been known for at least 4,000 years to have profound
effects on the mind effects that have provoked dramatically divergent attitudes
towards it. Some societies have regarded cannabis as a sacred boon for mankind
that offers respite from the tribulations of everyday life, whereas others have
demonized it as inevitably leading to reefer madness. The debate between the
protagonists and prohibitionists has recently been re-ignited, but unfortunately
this debate continues mainly in ignorance of our new understanding of the effects
of cannabis on the brain and of studies that have quantified the extent of the
risks of long-term use.
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PerSPeCTiveS
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Cannabinoids and synaptic plasticity.
Endocannabinoids have emerged as essential
mediators of several forms of transient
(530 second) and long-term (longer than
1 hour) plasticity in the cortex, the limbic
system, the basal ganglia and the cerebel-
lum
27,3640
. So far, in all cases, endocan-
nabinoid-dependent plasticity is expressed
presynaptically as a decreased probability of
neurotransmitter release.
At the behavioural level, intact endocan-
nabinoid signalling is required for cerebel-
lum-dependent motor learning
41
and for
the extinction of aversive memories in the
amygdala
42
. At CA3CA1 synapses in
the hippocampus, endocannabinoids appear
to facilitate memory encoding. Activity-
driven synthesis of 2-arachidonylglycerol in
the dendritic spines of pyramidal neurons
leads to onerm oepression of neighbouring
GABA and cholecystokinin (CCK) termi-
nals, such that adjacent excitatory synapses
are primed for strengthening by a reduction
in their thresholds for onerm poeniaion
(lTP)
4346
.
As mentioned above, CB1 receptors
are present on glutamatergic terminals in
the hippocampus
29,47
, albeit at much lower
levels than on GABA and CCK terminals
30
.
It might be that in hippocampal circuits the
endocannabinoid system serves as a local
amplifier that comes ready equipped with
a self-limiting feedback mechanism. Thus,
although preferential inhibition of GABA
inputs amplifies neighbouring excitatory
synapses, prolonged or excessive excitation
releases additional endocannabinoids that
terminate further glutamatergic drive and
act in a neuroprotective fashion
48
[FC 2a}.
Experimental work using conditional
knockout mice has demonstrated that CB1
receptors on glutamatergic terminals are
both necessary and sufficient to protect
against experimentally induced hippocampal
seizures
49
.
In contrast to the subtle effects of endo-
cannabinoids, acute administration
of exogenous cannabinoids markedly
disrupts neuronal signalling and circuit
dynamics [FC 2b}. Consequently, THC and
other exogenous CB1-receptor agonists
decrease synchronized neuronal firing in the
hippocampus, inhibit theta oscillations
50
and
lTP
51
and, at the behavioural level, impair
learning and memory.
The acute effects of cannabis
Cannabis is so widely used because its effects
are enjoyable. The most frequently reported
reasons for taking it are pleasure-seeking
and liking the experience of being relaxed
or high
52,53
; a small but growing minority
take it for its possible medicinal properties.
However, its ability to induce paranoia
was noted as early as 1845. The French
psychiatrist Moreau de Tours, who experi-
mented in the appropriately named Club de
Haschischins, published the results of stud-
ies in which he took cannabis himself (most
probably up to several hundred milligrams)
and gave it to some of his students and
patients. He concluded that cannabis could
precipitate acute psychotic reactions, gener-
ally lasting but a few hours, but occasionally
as long as a week
54
.
In 1958, Ames exposed medical staff to
controlled doses of cannabis
55
and noted
the emergence of delusions and visual
hallucinations. With higher doses, paranoid
ideas became common, with subjects
reporting fears of being hypnotized, of being
monitored by a hidden tape recorder and of
secretly being given shock therapy. Other
early studies
56,57
confirmed the ability of can-
nabis and THC to induce visual and auditory
hallucinations and persecutory delusions
58,59
.
Recently, DSouza and colleagues investigated
the acute effects of intravenous administra-
tion of 2.5 and 5 mg of THC in a double-
blind placebo-controlled study
60
, and found
that THC produced transient psychotic
symptoms that were dose-dependent.
Of the other constituents of cannabis,
cannabidiol (CBD) has aroused the most
interest. CBD is not hallucinogenic and, in
contrast to THC, it appears to have anxio-
lytic properties; surprisingly, it has even been
suggested to have antipsychotic effects
61
.
Effects on cognition. Acute administration
of cannabis causes impairment of cognitive
functioning
60,62
, specifically in executive
functions, such as attention and working
memory, and in hippocampus-dependent
learning and memory. The latter is not
surprising considering that, as described
above, endocannabinoids are key compo-
nents in the neuroplastic mechanisms that
are believed to underlie these processes. The
effect of the different constituents of can-
nabis on cognition varies, and therefore the
effect of the cannabis that an individual con-
sumes depends on the relative proportions
of THC to CBD. Most, but not all
63
, studies
have shown that THC impairs memory
function; by contrast, CBD administration
has been found to have no adverse effect on
Timeline | A brief history of cannabis
in the indus valley
civilization, cannabis is
regarded as one of five
sacred plants: a source
of happiness and
bringer of freedom.
The Pn-tsao Ching, the
oldest known pharmacopoeia,
describes medicinal
properties of cannabis, as well
as psychiatric side-effects
from excessive use.
60 nations sign the Uniform Drug Convention,
which pledges to end cannabis use within 25 years.
The link between
cannabis use and
the development
of schizophrenia
is shown for the
first time
78
.
The seven-volume report of
the indian Hemp Drugs
Commission concludes that
There is no evidence of any
weight regarding mental and
moral injuries from moderate
use of these drugs.
151
recreational use of
cannabis is banned in
the United Kingdom.
The Marijuana Tax Act effectively
prohibits recreational cannabis
use in the United States.
Cannabis is removed
from the American
Pharmacopoeia.
Mechoulam and
colleagues isolate and
subsequently synthesize

9
-tetrahydrocannabinol
(THC)
152
.
Groups such as NOrML (National Organisation for the
reform of Marijuana Laws), in the United States, and
SOMA, in the United Kingdom, lobby for the
legalization of cannabis. Over 3,000 people attend a
smoke-in in Hyde Park, London.
it becomes clear that
the psychological
effects of cannabis
are attributable to
THC.
in the Netherlands, The Opium
Act separates cannabis from
hard drugs. Subsequently, the
sale of cannabis is tolerated
under strict conditions. in the
United States, government
funding for medical research on
cannabis is banned.
The National institutes of Health
sponsored relman study concludes
that there is no evidence that
cannabis causes permanent health
damage, affects brain structure,
is addictive or leads to harder
drug [use]
153
.
2727 bc ~1200 bc 1894 1928 1937 1942 1961 1965 1967 1970 1976 1982 1987
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2007 Nature Publishing Group

cognition in animals
64
, and it might even
reverse the working memory deficits that are
induced by THC
65
.
People who use cannabis chronically show
cognitive impairment, but there is contro-
versy over whether this impairment persists
after the drug use has ceased. For example,
Fried et al. found no evidence of cognitive
deficits in cannabis users after three months
of abstention
66
, whereas Bolla et al. found
persisting deficits in decision-making and
brain activity among heavy cannabis users
who had been abstinent for 25 days
67
. One
possible explanation for these contradictory
findings is that the effects of cannabis on cog-
nition might depend on the age at which the
use of the drug began. Accordingly, in one
study of adults who regularly used cannabis,
cannabis use before, but not after, the age of
16 predicted poorer performance in a task
that required focused attention
68
. Similarly,
Pope and colleagues found that the initiation
of cannabis use before, but not after, the
age of 17 was associated with lower verbal IQ
scores in long-term heavy cannabis users
69
.
Animal studies that address whether the
cognitive effects of cannabis persist are few
in number, but their results are intriguing. In
rats that were chronically treated with THC,
hippocampal lTP was abolished for 3 days
following the last dose of THC, but it had
recovered completely after 14 days
70
. Similar
to findings in humans, immature, but not
adult, rats that were repeatedly exposed to a
potent CB1 agonist showed deficits in work-
ing memory and sensorimoor ain, and
displayed increased social anxiety even after
a drug-washout period of more than
20 days
71,72
.
Cannabis and the risk of psychosis
It has long been accepted that cannabis
intoxication can cause brief psychotic epi-
sodes
7375
, as can intoxication with a number
of other psychoactive drugs, such as amphet-
amines, cocaine, ketamine and phencyclid-
ine. From the 1990s onwards, reports started
to appear that demonstrated that, among
patients with established psychosis, those
who persisted in smoking cannabis had a
worse outcome than those who did not
76
. For
example, it was shown that continued use
of cannabis by people with a recent onset of
psychosis was associated with earlier relapse
of psychosis, more frequent hospitalization
and poorer psychosocial functioning over
the next 4 years
77
.
Numerous studies have shown that psy-
chotic patients take more cannabis than the
populations from which they are drawn.
But does cannabis actually cause psycho-
sis? In an attempt to answer this question,
researchers have carried out longitudinal
studies in general populations and related
cannabis consumption to subsequent onset
of psychosis. Thus, Andreasson et al.
78
, who
examined almost 50,000 young Swedish
male conscripts, found that men who had
smoked cannabis by the age of conscrip-
tion had double the risk of schizophrenia
in the ensuing 15 years. In addition, they
found that men who had smoked cannabis
on at least 50 occasions were six times
more likely to later receive a diagnosis of
schizophrenia. These findings were con-
firmed in a follow-up study of the cohort
25 years later
79
.
In another influential study, a birth
cohort of 1,034 children born in Dunedin,
New Zealand, were asked about their drug
consumption at the ages of 15 and 18, and
at 26 years of age 96% of the sample were
interviewed using a standardized psychiatric
assessment
80
. Those who had used cannabis
by the ages of 15 or 18 reported significantly
more psychotic symptoms at 26 years of age
compared with non-users. Furthermore,
10% of those who used cannabis by the age
of 15 were diagnosed with schizophreniorm
psychosis when they were 26 years old,
compared with 3% of the non-using control
group.
Another seven cohort or general-
population studies have reported similar
findings. These are summarized in ABLF !,
and have been extensively reviewed
8183
.
Criticisms. Some have claimed that the
studies discussed above might have been
confounded by the effect of other psychoac-
tive drugs, such as amphetamines and lSD,
which are known to be psychotogenic.
However, the association between cannabis
use and later schizophrenia in the Dunedin,
Dutch and Swedish studies held even when
the researchers adjusted for the use of other
psychotogenic drugs
79,80,84
.
A second criticism has been that the can-
nabis might have been taken in an attempt to
self-medicate against psychotic symptoms.
The best information concerning this comes
from the Christchurch study, in which
data on both cannabis use and psychotic
symptoms were collected from a cohort
that was studied at the ages of 18, 21 and 25
[RFFS 85,86}. The investigators were therefore
able to study both the effects of cannabis use
on later psychotic symptoms and also the
Timeline | A brief history of cannabis
The cannabinoid
1 (CB1) receptor is
cloned by Bonner
and colleagues
12
.
A leading British newspaper,
The independent on Sunday,
launches a decriminalize
cannabis campaign.
The first evidence that
endocannabinoids
mediate spike-timing-
dependent plasticity is
discovered
157
.
The first
endocannabinoid is
discovered and
termed anandamide
24
.
Cannabinoid agonists are
shown to reduce spasticity
in an animal model of
multiple sclerosis
155
.
Cannabis receptors
are discovered by
Howlett and
Devane
11
.
Sr141716 (rimonabant), the first
selective CB1 antagonist, is
discovered
154
. Germany
decriminalizes possession of small
quantities of cannabis for occasional
use. in the United Kingdom, the
maximum fine for possession
increases from 500 to 2500.
A second
endocannabinoid,
2-arachidonylglycerol,
is identified
25
.
endocannabinoids are
shown to inhibit the
release of amino-acid
neurotransmitters in the
hippocampus and the
cerebellum
27,156
.
endocannabinoids are
shown to be involved
in long-term synaptic
plasticity
37, 38
.
in the United Kingdom,
cannabis is moved from
a Class B to a Class C
drug; possession drops
to a maximum 2 year,
rather than 5 year,
prison sentence.
in Canada, a
cannabis-based
medicine is
licensed for the
treatment of
spasticity in
multiple
sclerosis.
1988 1990 1992 1994 1995 1997 2000 2001 2002 2003 2004 2005
PersPecti ves
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effect of psychotic symptoms on later canna-
bis use. As expected, cannabis use at the age
of 18 was associated with more psychotic
symptoms 3 and 7 years later. However,
the presence of psychotic symptoms at the
age of 18 appeared to inhibit, rather than
encourage, subsequent cannabis use. This
suggests a causal link between cannabis
use and the development of psychotic
symptoms and does not support the
self-medication explanation.
Thus, the epidemiological evidence
strongly suggests, although it cannot
prove, that heavy cannabis use increases
the risk of both psychotic symptoms and
schizophrenia. These conditions have a mul-
tifactorial aetiology in which a number of
environmental factors interact with a genetic
predisposition to cause illness
87,88
. Recent
meta-analyses have suggested that cannabis
acts as a componen cause that increases the
risk of psychotic illness between 1.4 and 1.9
times, and that might account for between
8% and 14% of cases of schizophrenia in
different countries
82,83
.
Few studies have investigated a possible
link between cannabis use and more com-
mon psychiatric disorders. In their meta-
analysis, Moore and colleagues came to the
conclusion that the evidence for an effect
of cannabis use on anxiety, depression and
suicide was much less convincing than that
concerning psychosis
83
.
How might cannabis cause psychotic
symptoms? Acutely psychotic patients
show oopamine sensiizaion. For example,
they release excessive striatal dopamine in
response to an amphetamine challenge, and
the degree of dopamine release correlates
positively with the severity of the psychotic
symptoms
89
. The probable mechanism is the
increased dopamine
90
resulting in increased
attention and excessive significance
(salience) being attributed to everyday
stimuli
91
. In this way, an unexpected sound,
the comments of a Tv newsreader or
eye contact with a stranger, for example,
are transformed from trivial everyday
occurrences into highly salient events of
great personal meaning to the psychotic
individual. Delusions can be understood as
an attempt to explain these experiences and
resolve the resultant perplexity, confusion
and dysphoria
92
.
Cannabis markedly increases dopamin-
ergic neuronal firing, including burst-firing,
and increases the release of dopamine at
terminal fields in the striatum
9396
. It is
tempting therefore to suggest that this is the
mechanism by which it exerts its psychoto-
genic effects. No investigations have directly
tested this in humans, although in one imag-
ing study a subject broke the protocol by
smoking cannabis during a pause between
imaging sessions, and the resulting brain
scans showed evidence that suggested the
occurrence of a cannabis-induced increase
in synaptic dopaminergic activity
97
.
Who is vulnerable? Why do only a small
minority of people who take cannabis, even
in large quantities, develop psychoses?
Individuals differ in their sensitivity to acute
administration of THC, with a minority
developing full-blown paranoia in response
to doses that barely have an effect in others
98
.
verdoux studied the acute effects of cannabis
in everyday situations, and assessed her
subjects using a questionnaire that meas-
ured subclinical psychotic experiences
99
.
Individuals without evidence of any predis-
position to psychosis generally responded
to cannabis by feeling more at ease with the
world, and experienced only minor per-
ceptual changes. However, those who were
identified as psychosisprone reported more
marked perceptual changes, and feelings of
increased suspicion and hostility after taking
cannabis
53
.
Nature Reviews | Neuroscience
>8% of population
58% of population
15% of population
<1% of population
Abuse extent unknown
Data not available
Figure 1 |Globalcannabisusebetween2003and2004.The map shows
the prevalence of cannabis use around the world between 2003 and 2004.
Darker colours indicate higher levels of cannabis use, with the darkest col-
our indicating that >8% of the population have used cannabis during the
previous year. Grey areas indicate countries for which data were not avail-
able; yellow areas indicate countries for which the extent of cannabis use is
unknown. Figure reproduced, with permission, from RFF !29 (2006)
United Nations Office on Drugs and Crime.
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Nature Reviews | Neuroscience
Glu
Glu
Glu
Glu
G
i/o
CB1
CB1
CB1 CB1
Ca
2+
Excitatory projection
from CA3
GABA/CCK
inhibitory
interneuron
MAGL
MAGL
Glu
Glu
G
i/o
Excitatory projection
from CA3
GABA/CCK
inhibitory
interneuron
GABA
A
GABA
A
mGlu1
GABA
GABA
GABA
GABA
GABA GABA
G
i/o
Glu Glu Glu
G
q
PLC
B
NMDA AMPA
PIP
2
IP
3
DAG
+
Ca
2+
Ca
2+
Ca
2+
Ca
2+
Dendrites of a CA1 pyramidal neuron
Dendrites of a CA1 pyramidal neuron
DAGL
DAGL
T?
T?
T?
Glu
Glu
Glu
Glu
MAGL
CB1
CB1
CB1 CB1
MAGL
Ca
2+
GABA
GABA
GABA
GABA
GABA GABA
G
i/o
G
i/o
mGlu1
G
q
PLC
B
PIP
2
NMDA AMPA
THC
THC
THC
a
b
GABA
A
GABA
A
2-AG
2-AG
T?
Henquet and colleagues prospectively
studied 2,400 young Germans. People
who were categorized as psychosis-prone
at baseline were no more likely than the
rest of the sample to use cannabis 4 years
later. However, among psychosis-prone
individuals, use of cannabis at baseline was
associated with a 24% increased risk for
psychotic symptoms at follow-up, whereas
in non-predisposed individuals who used
cannabis the risk was increased by only 6%
[RFF !00}. Thus, psychosis-prone individuals
were especially likely to develop psychotic
symptoms after using cannabis.
Caspi and colleagues reasoned that this
vulnerability might have a genetic basis. They
therefore studied how the interaction between
cannabis use and variation in the gene that
encodes catechol-O-methyltransferase
(COMT), an enzyme that is involved in the
breakdown of dopamine in the synapse, cor-
related with the risk of psychosis in subjects
in the Dunedin study that was discussed
earlier. Owing to a functional polymorphism
that involves a val-to-Met substitution at
codon 158, this gene has two common allelic
variants that influence the efficiency with
which dopamine is broken down in the pre-
frontal cortex. The val allele is thought to be
associated with increased dopamine levels in
Figure 2 |endocannabinoidsandTHcaffect
neurotransmission in the hippocampus.
a | endocannabinoids fine-tune neurotransmis-
sion. in the CA1 area of the hippocampus,
pyramidal neurons synthesize and release the
endocannabinoid 2-arachidonylglycerol (2-AG),
which acts at cannabinoid 1 (CB1) receptors on
adjacent nerve terminals. Synthesis of 2-AG is
driven by the stimulation of the metabotropic
glutamate receptor mGlu1, or by Ca
2+
entry
through voltage-operated channels
36
. Compelling
pharmacological evidence indicates the exist-
ence of an as-yet uncharacterized bidirectional
endocannabinoid transporter (T?)
142
. Consistent
with a retrograde mode of action for 2-AG, the
2-AG-synthetic enzyme sn1 diacylglycerol lipase
(DAGL) is localized to dendritic spines
28,29
,
whereas the 2-AG-catabolic enzyme monoacyl-
glycerol lipase (MAGL) is localized to presynaptic
terminals
143145
. endocannabinoid-dependent
plasticity is expressed presynaptically as a tran-
sient (530 second) or prolonged (longer than 1
hour) reduction in neurotransmitter release
36
.
inhibitory GABA (-aminobutyric acid) and chole-
cystokinin (CCK) terminals in the hippocampus
express more CB1 receptors than do excitatory
terminals
30
, and consequently they are more
sensitive to cannabinoids (reflected pictorially
by the use of solid and dashed arrows to repre-
sent the effects of 2-AG on inhibitory and excita-
tory terminals, respectively)
30,146
. in the CA1 area,
locally released 2-AG depresses GABA inhibitory
tone, thereby facilitating long-term potentiation
(LTP) at adjacent glutamatergic excitatory
synapses
4346
. CB1 receptors on glutamatergic
terminals might serve to limit the extent of 2-AG
synthesis and arrest the progression to seizures
and excitotoxicity
48,49
. b |
9
-tetrahydrocannabi-
nol (THC) disrupts neuromodulation in the hip-
pocampus. exogenous cannabinoids, such as
THC, disrupt rather than mimic the subtleties of
the endocannabinoid system in the hippocam-
pus. THC inhibits the long-term-potentiation of
CA3CA1 synapses by activating CB1 receptors
on glutamatergic terminals, inhibiting Ca
2+
influx
and suppressing glutamate release
36,51
. This
mechanism appears to underlie the detrimental
effect of THC on hippocampus-dependent learn-
i ng and memory
36, 51
. AMPA, -ami no-3-
hydroxy-5-methyl-4-isoxazolepropionic acid;
DAG, diacylglycerol; G
i/o
and G
q
, G-proteins; iP
3
,
inositol trisphosphate; NMDA, N-methyl d-
aspartate ; PiP
2
, phosphatidylinositol-4,5-
bisphosphate; PLC, phospholipase C

.
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Nature Reviews | Neuroscience
Cannabis users
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s

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i
t
h

s
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h
i
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o
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e
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15
Met/Met Val/Met Val/Val
Genotype
midbrain neurons that project to the ventral
striatum
101
. Caspi and colleagues found that
the use of cannabis in adolescence had no
effect on the subsequent risk of psychosis
in individuals who were homozygous for
the COMT Met allele. However, adolescent
smokers who were homozygous for the val
allele were at least five times more likely to
develop schizophreniform psychosis than
were people with the same genotype who did
not take cannabis
102
[FC 3}.
The number of psychotic subjects in the
Caspi et al. study is small, and as yet there
has been no direct attempt at replicating
the study in an epidemiological sample.
However, examining the COMT-variation
cannabis-use interaction experimentally,
Henquet gave study volunteers 300 g of
THC per kg of body weight, or a placebo,
and noted that carriers of the COMT
val allele were more likely to develop an
impairment of memory and attention than
carriers of the Met allele. Those with the
homozygous val genotype were also more
sensitive to the effects of THC on psychotic
symptoms, but this was dependent on their
pre-existing proneness to psychosis
103
.
Is cannabis addictive?
Epidemiological surveys show that approxi-
mately one in nine cannabis users satisfy the
clinical criteria for dependence on canna-
bis
104
[B\ !}. Although cannabis dependence
is moderate rather than severe, the number
of people requesting treatment for it has
been rising, particularly in Australia and the
United States, where between 1993 and 1999,
the annual number doubled to 232,105.
Animal studies support the idea that
cannabis can induce dependence. Animals
will press levers repeatedly to obtain intra-
venous injections of addictive drugs such
as morphine and cocaine
105,106
. Similarly,
rodents and monkeys self-administer THC
at doses that are comparable to those taken
by humans who smoke cannabis
107110
. When
given a choice, laboratory animals will
choose a compartment that has been repeat-
edly paired with the experience of receiving
an addictive drug, such as heroin, over one
that is associated with receiving a placebo.
THC also produces this effect, but only at
low doses
107,110
; at high doses THC appears to
induce conoiioneo paceaversion
110
.
Following repeated dosing, tolerance
develops to the psychological and analgesic
effects of THC. Tolerance is mediated
through the internalization of CB1 recep-
tors
5,34
. Some researchers have pointed to
the lack of a significant cannabis withdrawal
syndrome as evidence of non-addictiveness.
However, the CB1-receptor antagonist
rimonabant can trigger a pronounced can-
nabis withdrawal reaction in animals and
humans
5
. It seems that, in the usual situation
among cannabis users, the slow clearance of
cannabis from the body masks withdrawal
symptoms.
Habit-forming drugs share the ability
to increase the release of dopamine in the
nucleus accumbens, and this property is
believed to be central to the addictive proc-
ess
111
. Cannabis is no exception
112
. Indeed,
the ability of alcohol, nicotine and opiates
to enhance dopamine release in the nucleus
accumbens is blocked by CB1-receptor
antagonists and is absent in mice that lack
the CB1 receptor
110
. Similarly, at the behav-
ioural level, knocking out the CB1-receptor
gene or blocking the receptor in rodents
abolishes conoiioneo pacepreerence by, and
self-administration of, alcohol, nicotine
and opiates
110
.
Cannabis use and hard-drug abuse
Abusers of hard drugs most commonly
report that cannabis was the first recrea-
tional drug, other than alcohol or tobacco,
that they used
113
. Two main theories have
been proposed to explain this finding. First,
the gateway theory argues that cannabis use
can facilitate the subsequent use or misuse
of other drugs
114
. Second, the correlated
vulnerabilities theory postulates that some
individuals have a general predisposition to
using drugs, including cannabis; this could
Table 1 | General population studies of the effect of cannabis use on the risk of psychosis
countryinwhichthestudywas
conducted
numberof
participants
Followup oddsratio(95%
confidenceinterval)
studydesign references
United States 4,494 NA 2.4 (1.2, 7.1) Population based 147
Sweden 50,053 25 years 2.1 (1.2, 3.7) Conscript cohort 78,79
The Netherlands 4,045 3 years 2.8 (1.2,6.5) Population based 84
israel 9,724 415 years 2.0 (1.3, 3.1) Population based 148
New Zealand (Christchurch) 1,265 3 years 1.8 (1.2, 2.6) Birth cohort 85
New Zealand (Dunedin) 1,253 15 years 3.1 (0.7,13.3) Birth cohort 80
The Netherlands 1,580 14 years 2.8 (1.79,4.43) Population based 149
Germany 2,436 4 years 1.7 (1.1, 1.5) Population based 100
United Kingdom 8,580 18 months 1.5 (0.55,3.94) Population based 150
NA, not applicable.
Figure 3 |Modulationoftheeffectofadoles-
centcannabisuseonpsychosisbycoMT
genotype.Owing to a functional polymorphism
that involves a val-to-Met substitution at codon
158, the gene for catechol-O-methyltransferase
(COMT) has two common allelic variants that
influence the efficiency with which dopamine is
broken down in the prefrontal cortex. One study
that genotyped this polymorphism in 800 indi-
viduals found that cannabis use during adoles-
cence significantly increased the risk of develop-
ing a schizophreniform disorder at age 26, but
only in those individuals who carried one or two
of the val alleles. Although the number of psy-
chotic subjects in this study was small, the results
indicate that vulnerability to cannabis-induced
psychosis might have a genetic basis. Figure
modified, with permission, from RFF !02 (2005)
elsevier Science.
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be mediated by a risk-taking personality
115
.
Until recently, most experts favoured the
second of these explanations, but recent
evidence has revived the gateway theory.
Fergusson and co-workers used data
from the Christchurch study, which we dis-
cussed earlier, to examine the developmental
sequence of drug use from 15 to 21 years
of age. Early use of cannabis was associated
with an increased risk of subsequent abuse
of or dependence on other drugs, even after
family and social circumstances were
controlled for in the analysis
116
.
lynskey and colleagues examined the
possible mechanisms behind this finding
by studying the drug histories of more than
300 twin pairs who were discordant for
early cannabis use. The individuals who
had used cannabis by the age of 17 were
between two and five times more likely
than their non-using co-twins to report
subsequent other drug use, and drug and
alcohol dependence. These associations
persisted when early-onset alcohol or
tobacco use, childhood sexual abuse and
conduct disorder were controlled for
117
.
Thus, either a pharmacological effect of
cannabis increases the probability of transi-
tion to hard drugs, or an environmental
factor that is unique to the drug-taking
co-twin underlies both adolescent cannabis
use and later hard-drug use.
Results from animal studies support the
first possibility: they show that THC affects
the developmental plasticity of the reward
system. Thus, pre-treatment of rats with
THC from postnatal days 4 through 14 low-
ers the threshold for heroin-induced condi-
tioned place-preference at 8 weeks of age
118
.
Furthermore, exposure to THC prenatally
or during adolescence enhances opiate self-
administration in adulthood
119121
, but only
under a fixed-ratio-1 schedule (in which
one lever press results in one injection).
This indicates that pre-exposure to THC
does not alter heroins rewarding efficacy
per se, but that the enhanced responses in the
fixed-ratio schedule might be explained by
crossoerance
119
. This possibility is supported
by an impressive body of pharmacological
literature that describes multiple interactions
between the endocannabinoid and opiate
systems and includes evidence for cross-
tolerance (for a review, see RFF !!0).
A frequent criticism of the idea that can-
nabis is a gateway drug has been that most
hard-drug users started smoking tobacco
before they began using cannabis. This was
indeed the traditional pattern, and longitu-
dinal studies of teenagers from the United
States that were carried out in the 1970s
and 1980s reported that tobacco use
preceded and predicted subsequent use of
cannabis
122
. However, more recent studies
have shown that, in young people, use of
tobacco has decreased whereas use of can-
nabis has increased, such that cannabis use
now appears to be a predictor of tobacco
smoking. Thus, studies in both Australia
and Scotland have shown that cannabis
use during the teens and early adulthood is
associated with an increased subsequent risk
of initiation of tobacco use and progression
to nicotine dependence
123,124
.
Nevertheless, whether early use of can-
nabis increases the risk of subsequent abuse
of hard drugs remains highly contentious.
Most cannabis users do not escalate to the
use of heroin or cocaine, but the recent stud-
ies have put the gateway theory back into
contention.
Cannabis and society
Historically, some societies have idealized
cannabis whereas others have demonized it
and, recently, Western society has tended to
oscillate between the two. In reality, as canna-
bis derivatives have the potential for causing
both good and harm, the important question
for society is how to maximize the former
and minimize the latter.
Cannabis-based medicines. Interest in the
potential value of cannabis-based medicines
has been steadily rising. In the 1980s, THC
(Dronabinol) was licensed for the treat-
ment of chemotherapy-induced nausea and
vomiting and for the stimulation of appetite
in AIDS patients. More recently, trials have
shown that cannabis-based medicines pro-
vide symptomatic relief for spasticity, pain
and sleep disturbance in patients with mul-
tiple sclerosis
125127
. In 2005, Sativex, which
is an oromucosal spray that contains THC
and CBD in a 1/1 ratio, gained approval in
Canada for the relief of neuropathic pain
in people with multiple sclerosis, and
recently, Health Canada announced its
intention to approve Sativex for the treat-
ment of cancer pain. Cannabis-based
medicines are also promising treatments for
particular symptoms of Tourettes syndrome
and glaucoma, and might prove useful as
neuroprotective agents in the treatment of
head injury, inflammatory disorders and
some forms of cancer
2,4
.
The CB1-receptor antagonist SR141716A
(rimonabant) has been shown to be an
effective treatment for nicotine dependence;
indeed, pre-clinical studies suggest that CB1-
receptor antagonists such as rimonobant
might be effective against craving in a range
of disorders, such as substance abuse and
obesity
110,128
. However, there have been
concerns that rimonabant might be associ-
ated with depression and suicidal thoughts
and, although it is available in Europe for the
treatment of metabolic syndrome associated
with obesity, the FDA has not yet granted a
licence for it in the United States.
It is likely that further advances in our
understanding of the endocannabinoid sys-
tem will lead to the development of new can-
nabis-based medicines. In a rational world,
the introduction of such medicines would
not be influenced by attitudes towards the
recreational use of cannabis. Sadly, however,

Box 1 | Addiction and dependence
Addictive behaviour includes not only the misuse of psychoactive substances, but also other
activities, such as excessive gambling, eating and sexual behaviour. It is defined as a repetitive
pattern that increases the risk of disease and associated personal and social problems. The
individual usually has a loss of control and seeks immediate gratification, then suffers delayed,
deleterious effects. They often relapse when trying to quit.
The concept of dependence was developed by Edwards and Gross in 1976 [RFF !0}; it is applied
almost exclusively to drugs. In the International Classification of Mental Disorders 10 (ICD 10),
three or more of the following criteria are required for the diagnosis of the dependence
syndrome
141
:
Increased tolerance to the drug (the requirement that greater dosages of a given drug be used to
produce an identical effect as time passes).
A physiological withdrawal state when substance use has ceased or been reduced. This is usually
evidenced by the need to use the same substance to relieve or avoid the withdrawal symptoms.
Difficulties in controlling substance-taking behaviour in terms of its onset, termination or
amount used.
Increased salience of drug-seeking behaviour (obtaining and using the drug becomes the priority
in the persons life).
Narrowing of the behavioural repertoire of the drug taking.
Rapid reinstatement after abstinence.
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Nature Reviews | Neuroscience
Africa
Asia
Oceania Europe
South America (non-NAFTA)
North America (NAFTA)
Trend
Other
Near and Middle East/south-west Asia
North Africa
West and central Europe
8,000
7,000
6,000
5,000
4,000
3,000
2,000
1,000
0
1
9
8
5
1
9
8
7
1
9
9
1
1
9
8
9
1
9
9
3
1
9
9
5
1
9
9
7
1
9
9
9
2
0
0
1
2
0
0
3
2
0
0
5
M
e
t
r
i
c

t
o
n
s
M
e
t
r
i
c

t
o
n
s
0
1
9
8
5
1
9
8
7
1
9
9
1
1
9
8
9
1
9
9
3
1
9
9
5
1
9
9
7
1
9
9
9
2
0
0
1
2
0
0
3
2
0
0
5
500
1000
1,500
Year
Year
the two tend to become confused in the pub-
lic mind, and there is a danger that useful
medicines might not be licensed because
of rising concerns about the recreational
use of cannabis.
Recreational use of cannabis. This rising
concern led the United Nations to devote
the bulk of its 2006 Annual Report on Drug
Abuse to cannabis
129
. The report estimates
that 160 million people, equivalent to 4% of
the worlds adult population, use cannabis
each year. The report indicates that con-
sumption rose in all continents during the
last quarter of the twentieth century, with
consumption currently highest in Western
Europe, North America and, in particular,
Australia and New Zealand. Traditionally,
cannabis has been mainly available as a herb
or as resin. The herb (known as marijuana,
grass and ganja, among others) is comprised
of the flowering tops and leaves of the plant,
whereas resin (also known as hashish)
consists of the secretions of the plant that are
emitted when it is flowering. World produc-
tion of the herb almost doubled between
the early 1990s and 2005, reaching a total of
45,000 metric tons; the production of resin
has also risen steadily, reaching a global total
of 7,500 tons in 2004. Seizures show the
same trend [FC }.
There are two other recent trends in
cannabis use and production. First, in many
countries the concentration of THC in street
preparations of cannabis has risen. This is
a consequence of the availability of more
potent varieties of cannabis, which are vari-
ously termed sinsemilla or skunk; these are
often produced indoors using greenhouse
techniques. Until recently, the concentra-
tion of THC in cannabis was 14%, but by
2003, the average concentration in street
preparations seized in the USA had risen to
7%. In European countries cannabis potency
also increased: between 1996 and 2004, the
average THC concentration in sinsemilla
doubled from 6% to 12% in England and
Wales, and at the extreme it reached 20% in
some forms in the Netherlands
129
.
A second cause for concern is the
decreasing age of first-time cannabis users.
For example, between 1992 and 1996, the
number of children in the Netherlands who
had started using cannabis by the age of 13
doubled
130
. In Europe as a whole, 40% of
1516-year-old adolescents have now tried
the drug
129
. However, although there are
suspicions that adolescents are more prone
to the cognitive and psychotogenic effects
of cannabis, this is far from proven
80,83
.
Furthermore, since 2005, the production and
consumption of cannabis have fallen slightly
on all continents except Africa
131
. This might
be a consequence of a greater awareness of
the risks of cannabis among young people
131
.
Legal policies. There is huge variation both
in the prevalence of cannabis use and in the
legal constraints on its use in different coun-
tries. The two are not necessarily linked. For
example, both Sweden and the Netherlands
provide models that have been much
admired. Sweden has a highly restrictive
policy, low cannabis consumption and few
problems associated with cannabis use. The
Netherlands has a liberal approach in which
cannabis is available in designated coffee
shops, and it has a consumption level that
is near the European average but is well
below that of France, Spain and the United
Kingdom.
The confusion concerning legal policies is
exemplified by the United Kingdom, where
there has been a raucous argument between
pro- and anti-cannabis lobbies
132
. Following
the advice of the Advisory Council on
Misuse of Drugs that use of cannabis had no
serious adverse psychological effects
133
, the
UK Government decided in 2002 to reduce
the illegality status of cannabis so that pos-
Figure 4 | Worldwide trends in cannabis
seizures.The graphs show the amounts of can-
nabis herb (top panel) and resin (bottom panel)
that were seized in the period 19852005, broken
down by region. The overall trend in herb seizures
is represented by the red line. NAFTA, North
American Free Trade Agreement. Figures repro-
duced, with permission, from RFF!3! (2007)
United Nations Office on Drugs and Crime.
Glossary
Component cause
A risk acor ha acs wih some oher acor or acors o
have a causa inuence on he risk or a oisease
Conditioned place-aversion
he aversion o environmena simui ha have previousy
been associaeo wih a neaive rewaro
Conditioned place-preference
he preerence or environmena simui ha have
previousy been associaeo wih a posiive rewaro or oru
eecs
Cross-tolerance
A oecrease in he response o a subsance as a resu o
coninueo exposure o a oieren subsance ha has a
simiar pharmacooica acion
Dopamine sensitization
he process whereby repeaeo, inermien simuan
exposure proouces a permanen chane in oopamineric
responses
Long-term depression
[LD} An enourin oecrease in he srenh o
neuroransmission a a synapse LD is beieveo o
unoerpin earnin ano memory
Long-term potentiation
[LP} An enourin increase in he srenh o
neuroransmission a a synapse LP is beieveo o
unoerpin earnin ano memory
Psychosis
A mena oisurbance characerizeo by aberraions o
percepion [haucinaions} ano houh [oeusions} ha
causes a person o ose ouch wih exerna reaiy
Psychosis-proneness
An increaseo eneic vunerabiiy o oeveopin psychoic
iness, as evioenceo by he occurrence o subcinica
psychoic experiences
Schizophreniform psychosis
A schizophreniaike psychosis in which he sympoms as
or a eas ! monh [as opposeo o 6 monhs or a
oianosis o schizophrenia}
Sensorimotor gating
he neura ierin process ha aows aenion o be
ocuseo on one simuus
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2007 Nature Publishing Group

session of small quantities became largely a
non-arrestable offence. However, no sooner
had they announced their decision than
reports of the relationship between cannabis
use and psychosis started to appear.
The implications of this link have been
much discussed in the United Kingdom.
Hickman and colleagues predicted that by
2010 a substantial increase in the incidence
of schizophrenia should be apparent. Under
a conservative model in which heavy use
of cannabis carries a twofold risk of schizo-
phrenia, they calculated that the drug would
be responsible for 10% of new schizophrenia
cases, rising to 25% if light use of the drug
also carries this risk
134
. Recent studies by
Boydell and co-workers are compatible with
this view. During the period 19651999, the
incidence of schizophrenia in South london
doubled
135
, and there was a large increase
in the proportion of cases that had used
cannabis in the 12 months before diagnosis;
this increase was much greater than that in
non-schizophrenic controls
136
.
In consequence, British newspapers
and opposition politicians pressed for the
reinstatement of the previous classification,
oblivious to the fact that the reclassifica-
tion had actually been accompanied by a
decrease in the consumption of cannabis
131
.
In 2005, the Advisory Council on Misuse of
Drugs reversed its previous benign view
of cannabis and accepted the evidence that
linked cannabis to psychosis
137
. However, it
did not recommend a change in classifica-
tion; this was based on the consideration
that its overall harmfulness did not equate
with that of other drugs in the next category.
By 2007, the media clamour had reached
such a pitch that a further review of the
classification was announced.
Similarly confusing and contradic-
tory legal steps are being taken in other
countries. For example, the famously liberal
Netherlands have been closing coffee shops,
while by contrast Switzerland has come
near to legalizing cannabis in the face of an
increase in the incidence of schizophrenia
in young people
138
. Of course, decisions
concerning the legal status of cannabis
need to take into account a range of factors
other than health effects. For example, some
suggest that more harm comes from the
expensive enforcement of criminal penalties,
school dropout and the black-market that is
associated with the criminalization of can-
nabis than from the deleterious effects
of cannabis on mental health
139
. One thing is
certain: politicians find it difficult to balance
the enjoyment that cannabis brings to the
majority of users with the dependence,
cognitive difficulties and psychosis it
induces in a minority. Swings in popular
prejudice tend to push legislators towards
alternately tightening and loosening the
legal constraints on cannabis use. Public
education about the risks of excessive use of
cannabis appears to have a greater influence
on consumption levels than alterations in
the legislative status of cannabis; however
(and curiously), governments rarely adopt
this approach.
Robin M. Murray, Paul D. Morrison and
Marta Di Forti are at the Institute of Psychiatry,
Psychological Medicine, De Crespigny Park, Denmark
Hill, London, SE5 8AF, UK.
Ccile Henquet is at the Department of Psychiatry and
Neuropsychology, South Limburg Mental Health
Research and Teaching Network, EURON, Maastricht
University, Maastricht, the Netherlands.
Correspondence to R.M.M.
e-mail: Robin.murray@iop.kcl.ac.uk
ooi!0!038/nrn2253
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